Mechanistic Insights into the Antioxidant and Pro-oxidant Behaviors of Uric Acid in the Presence of Cu(II)

Quantum chemical calculations based on Density Functional Theory (DFT) were performed to investigate the antioxidant potency and pro-oxidant risk of uric acid upon coordination with copper(II) ions. Stable monodentate square-planar Cu(II)-urate complexes were employed as models to represent the metal–ligand interaction in aqueous environments. Antioxidant performance was evaluated using key thermodynamic descriptors, including bond dissociation enthalpy (BDE) and ionization energy (IE), along with detailed kinetic analysis of radical trapping with the hydroperoxyl radical (HOO • ) via formal hydrogen transfer (FHT), sequential proton loss electron transfer (SPLET), and single electron transfer proton transfer (SETPT) mechanisms. The free urate anion exhibits a low IE (91.2 kcal mol –1 ) and BDE (75.3 kcal mol –1 ). Metal coordination moderately increases these values. Kinetic analysis based on Marcus theory reveals that Cu(II) coordination shifts the SPLET pathway away from the inverted region, resulting in a significant acceleration of the electron transfer rate. The pro-oxidant behavior was assessed through the energetics of Cu(II) reduction by biological reducing agents. The Cu(II)-urate complexes exhibit a reduced propensity for reduction to Cu(I) compared to hydrated copper(II) ions. These findings underscore the critical role of the coordination environment in modulating antioxidant mechanisms, demonstrating how targeted metal–ligand interactions can sustain strong radical-scavenging activity while effectively suppressing unwanted redox cycling.